The chances for survival with HIV/AIDS have increased; millions of people will face the concomitant risk of old age plus HIV infection. We hypothesize that the increase in brain inflammatory drive decreases neuronal protein turnover through the ubiquitin-proteasome degradation pathway (Ub-prot), leading to accumulation of Ub-protein conjugates as observed pathologically in neurodegenerative diseases that cause dementia. AIM 1 will address the hypothesis neurochemically in a cross-sectional autopsy study of HIV infected human brain specimens in which neurocognitive function was measured prior to autopsy. Using fresh-frozen human brain specimens we will identify and measure the concentrations of HMW-Ub-conjugates, characterize the abnormal HMW-Ub-conj chemically, measure brain-specific proteolytic activity of the major proteasomal reactions, characterize subunit composition of the catalytic site of 20S Ub-prot particles and determine the cellular localization of the proteasome. Parametric comparison will be made between Ub-prot measurements and antemortem neurocognitive performance, and also with steady state concentrations of presynaptic proteins associated with learning and memory. Data available from brain bank subjects for analysis of covariance include the number of activated brain microglial cells and HIV RNA concentrations in brain, blood and cerebrospinal fluid (CSF). AIM 2 addresses the hypothesis mechanistically using HIV-infected adult human microglia and NT2.N human neurons in vitro. We will determine how HIV-infected adult human microglial cells induce an Ub-prot disturbance in differentiated human neuronal NT2 cells, which undergo cell death due to Ub-prot inhibition and inflammation both. Using HIV-conditioned media and NT2 neurons we will measure neuronal HMW-Ub-conj, enzyme activity and kinetics, 20S subunit composition as in AIM 1 and also, turnover of synaptic proteins via Ub-prot. AIM 3 addresses the hypothesis clinically in a longitudinal cohort of people with and without HIV infection that undergo regular neurocognitive and neurological testing. The rate of progression of cognitive function and brain atrophy will be assessed to determine if HIV, and age at entry are synergistic. The linkage between brain inflammation and altered neuronal protein turnover could lead to a unifying functional concept of dementia with application to HIV and aging both.